Novel Approaches to CD33-Directed Radioimmunotherapy

CD33 定向放射免疫治疗的新方法

• 批准号: 10523534
• 负责人: Roland Bruno Walter
• 金额: $ 62.35万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523534
• 关键词: Actinium; Acute Myelocytic Leukemia; Address; Animal Experiments; Antibodies; Antibody Therapy; Antibody-drug conjugates; Antigen Targeting; Antigens; Astatine; Biodistribution; Cell surface; Cells; Characteristics; Clinic; Clinical; Dangerousness; Daughter; Deposition; Diameter; Distal; Gemtuzumab Ozogamicin; Genetic Diseases; Glycoproteins; Goals; Half-Life; Hematopoietic; Human; Human Anti-Mouse Antibody; Immune system; Immunization; Immunocompetent; Immunotherapy; Isotopes; Label; Leukemic Cell; Life Extension; Malignant - descriptor; Membrane; Modeling; Mus; Neoplasms; Normal Cell; Nude Mice; Organ; PTPRC gene; Patients; Production; Property; Radiation; Radiation Tolerance; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Research Personnel; Risk; SET Domain; Safety; Testing; Therapeutic; Therapeutic Studies; Tissues; Toxic effect; Transplantation; Treatment Efficacy; Treatment outcome; Treatment-related toxicity; Variant; Xenograft Model; acute myeloid leukemia cell; arm; cell killing; clinical development; conditioning; cost; early phase clinical trial; ethnic minority population; humanized mouse; improved; improved outcome; in vivo; in vivo Model; interest; lead candidate; leukemia; leukemic stem cell; mouse model; multidisciplinary; novel; novel strategies; particle; preclinical study; therapeutic candidate; therapeutically effective; tumor

Antigen-specific immunotherapies have long been pursued for acute myeloid leukemia (AML). So far most exploited are antibodies targeting the membrane-distal V-set domain of CD33, a glycoprotein displayed on the cell surface of leukemic blasts in almost all cases and possibly leukemia stem cells in some. Improved survival of some patients with gemtuzumab ozogamicin validates this approach but many patients with CD33+ AML do not benefit from this antibody-drug conjugate, prompting interest in developing improved CD33-directed therapeutics. Because AML cells are exquisitely radiosensitive across the entire genetic disease spectrum, a- emitting radionuclides are ideal to arm anti-CD33 antibodies. Unlike b-emitters, they deliver a very high amount of radiation over just a few cell diameters, thereby enabling precise and efficient target cell kill (as few as 10 a- particle hits are sufficient to kill a malignant hematopoietic cell). Early clinical trials with an anti-CD33 antibody labeled with actinium-225 (225Ac-lintuzumab) have been conducted. Besides high cost, however, important shortcomings include the long half-life of 225Ac, leading to freely circulating radionuclide if not retained effectively in target cells, and the release of daughter radionuclides after decay of 225Ac with risk of associated toxicity to healthy tissues. We hypothesize that labeling with astatine-211 (211At), an a-emitter we have focused on because of its shorter half-life and because it decays without production of any long-lived or potentially dangerous daughter isotopes, will provide a novel, superior form of CD33-directed radioimmunotherapy (RIT). Using humanized mice, we have recently generated a panel of fully human antibodies recognizing either the V-set domain or, as the first group, the membrane-proximal C2-set domain of human CD33. Since the V-set but not C2-set domain is missing in some CD33 variants, C2-set domain-directed antibodies can recognize all naturally- occurring variants of CD33 (i.e. are “CD33PAN antibodies”). With these antibodies available, we now plan to optimize CD33-directed RIT for application in AML patients, focusing on 211At. To accomplish this task, we have assembled a multidisciplinary team of investigators with complementary expertise in developing radioimmunoconjugates and other antibody-based therapeutics for AML. Envisioning broad use, we will study 211At-CD33 RIT as “stand-alone” therapy and as augmentation of HCT conditioning, focusing on MHC- haploidentical in vivo models AML. Since many HCT candidates do not have an HLA-matched donor, facilitation of alternative donor HCT remains a critical unmet need, particularly for the extension of this lifesaving option to patients from ethnic minority groups. We expect results from our studies will be readily translatable into the clinic and are anticipated to have an important positive impact as they will provide the groundwork for a new treatment option for patients with AML and other CD33+ neoplasms, for whom current treatment outcomes are unsatisfactory.

抗原特异性免疫疗法长期以来一直被用于急性髓性白血病（AML）。到目前为止， 利用的是靶向CD 33的膜远端V-set结构域的抗体，CD 33是一种展示在细胞膜上的糖蛋白。 几乎所有病例中白血病母细胞的细胞表面，一些病例中可能是白血病干细胞。改善的存活 一些使用吉妥珠单抗的患者证实了这种方法，但许多CD 33 + AML患者 没有从这种抗体-药物缀合物中受益，促使人们对开发改善的CD 33-定向的免疫抑制剂产生兴趣。 治疗学由于AML细胞在整个遗传疾病谱中具有极高的放射敏感性， 发射放射性核素是理想的武装抗-CD 33抗体。不像b-发射体， 的辐射在几个细胞直径，从而能够精确和有效的靶细胞杀伤（少至10埃- 颗粒命中足以杀死恶性造血细胞）。抗CD 33抗体的早期临床试验 已经进行了用锕-225（225 Ac-lintuzumab）标记的研究。除了成本高，重要的是 缺点包括225 Ac的半衰期长，如果不能有效保留，导致放射性核素自由循环 在靶细胞中，以及在225 Ac衰变后子体放射性核素的释放， 健康的组织我们假设，用我们关注的α-发射体--<$211（211 At）标记， 它的半衰期较短，因为它衰变时不会产生任何长寿命或潜在危险的物质， 子同位素将提供一种新的、上级形式的CD 33-定向放射免疫疗法（RIT）。使用 在人源化小鼠中，我们最近产生了一组完全人类抗体， 结构域或作为第一组的人CD 33的近膜C2-set结构域。由于V型集，但不是 C2-set结构域在一些CD 33变体中缺失，C2-set结构域定向的抗体可以识别所有天然的- 在一些实施方案中，抗体是CD 33的存在变体（即“CD 33 PAN抗体”）。有了这些抗体，我们现在计划 优化CD 33定向RIT在AML患者中的应用，重点关注211 At。为了完成这项任务，我们必须 组建了一个多学科的调查小组，在开发 放射免疫缀合物和其他基于抗体的AML治疗剂。展望广泛的使用，我们将研究 211 At-CD 33 RIT作为“独立”治疗和HCT调节的增强，侧重于MHC- 单倍体相合的体内模型AML。由于许多HCT候选人没有HLA匹配的供体， 替代供体HCT仍然是一个关键的未满足的需求，特别是对于将这种救生选择扩展到 少数民族患者。我们希望我们的研究结果将很容易转化为临床 并预计将产生重要的积极影响，因为它们将为新的治疗方法提供基础 AML和其他CD 33+肿瘤患者的选择，其目前的治疗结果是 不满意。